Process for preparing 3,3′,6,6′-tetraalkyl-2,2′-biphenols and 3,3′,6,6′-tetraalkyl-5,5′-dihalo-2,2′-biphenols

ABSTRACT

A process for making a compound of the formula I

CROSS REFERENCE TO RELATED APPLICATIONS

This is a Divsional case, filed under 37 C.F.R. 1.153(b)and claimingpriority to U.S. patent application Ser. No. 09/994,098 filed Nov. 26,200 now U.S. Pat. No. 6,489,517.

FIELD OF THE INVENTION

This invention relates to a process for preparing3,3′,6,6′-tetraalkyl-2,2′-biphenols and3,3′,6,6′-tetraalkyl-5,5′-dihalo-2,2′-biphenols.

BACKGROUND OF THE INVENTION

Substituted biphenols such as 3,3′,6,6′-tetraalkyl-2,2′-biphenol;3,3′,4,4′,5,5′,6,6′-octaalkyl-2,2′-biphenols;3,3′,5,5′,6,6′-hexaalkyl-2,2′-biphenols;3,3′,5,5′-tetraalkyl-2,2′-biphenol;3-alkyl-5,5′,6,6′,7,7′8,8′-octahydro-2,2′-binaphthol;3,3′-dialkyl-5,5′,6,6′,7,7′8,8′-octahydro-2,2′-binaphthol and3,3′6,6′-tetralkyl-5,5′-dihalo-2,2′-biphenol are compounds that can beused to make phosphorus-based catalyst ligands. Such ligands includephosphines, phosphinites, phosphonites, and phosphites.Mono(phosphorous) ligands are compounds that contain a single phosphorusatom which serves as a donor to a transition metal, whilebis(phosphorus) ligands, in general, contain two phosphorus donor atomsand typically form cyclic chelate structures with transition metals.

In general, biphenols can be made by the oxidative coupling of(mono)phenols, but often other types of products, such as ketones, areobtained, and/or overall yields are poor for other reasons.

Phenols can be oxidatively coupled to make the corresponding biphenolsby the use of a variety of oxidizing agents, such as nitric acid, ferricchloride, potassium ferricyanide, chromic acid,2,3-dichloro-5,6-dicyanobenzoquinone and di-t-butyl peroxide.2,2′-Dihydroxy-3,3′-di-isopropyl-6,6′-dimethylbiphenyl can be preparedfrom 2-isopropyl-5-methyl-phenol with2,3-dichloro-5,6-dicyanobenzoquinone or di-t-butyl peroxide. SeeTetrahedron, 1875, 1971 and J. Chem. Soc., Perkin Trans. II, 587, 1983.Some of the oxidants and/or co-catalysts involve the use of relativelyexpensive and/or explosive (peroxides) compounds, which posedisadvantages for large scale commercial use.

Phenols can also be oxidatively coupled using a combination of atransition metal catalyst and an oxidizing agent such as persulfateanion or oxygen. See U.S. Pat. Nos. 6,077,979; 4,139,544; 4,132,722;4,354,048; and 4,108,908. See also J. Org. Chem. 1984, 49, 4456 and J.Org. Chem. 1983, 48, 4948. The cited patents disclose the use of oxygenas an oxidizing agent with various copper complexes as catalysts (copperchromite; copper acetate with sodium mercaptoacetate; copper acetatewith pentasodium/diethylenetriaminepentacetate; copper acetate with1,3-diamino-2-hydroxypropane-tetracetic acid). The examples in thepatents disclose the use of 2,6-disubstituted phenol or2,4-di-tert-butylphenol.

The use of copper amine catalysts, with oxygen as an oxidizing agent,has been described in connection with the oxidative coupling of2,4-di-tert-butylphenol, 2-methyl-4-tert-butylphenol,2-chlor-4-tert-butylphenol and 4-tert-butylphenol. See J. Org. Chem.1984, 49, 4456 and J. Org. Chem. 1983, 48, 4948.

There is a continuing need in the art for methods for making with decentyields substituted biphenols suitable for making phosphorous-basedcatalyst ligands.

SUMMARY OF THE INVENTION

In its first aspect, the present invention is a process for making acompound of the formula I

wherein

R¹ is C₁ to C₁₀ primary or secondary alkyl or cycloalkyl,

R² is C₁ to C₁₀ primary or secondary alkyl or cycloalkyl, and

X is H, Cl, Br, or I,

comprising:

(1) when X is Cl

(a) chlorinating a compound of the formula II

 at the 4-position thereof to produce a compound of the formula III

 wherein X is Cl,

(b) oxidatively coupling the compound of the formula III wherein X is Clto produce a compound of the formula I wherein X is Cl;

(2) when X is H

(a) chlorinating a compound of the formula II at the 4-position thereofto produce a compound of the formula III wherein X is Cl,

(b) oxidatively coupling the compound of the formula III wherein X is Clto produce a compound of the formula I wherein X is Cl, and

(c) dechlorinating the compound of the formula I wherein X is Cl toproduce a compound of the formula I wherein X is H; or

(3) when X is Br or I

(a) chlorinating a compound of the formula II at the 4-position thereofto produce a compound of the formula III wherein X is Cl,

(b) oxidatively coupling the compound of the formula III wherein X is Clto produce a compound of the formula I wherein X is Cl,

(c) dechlorinating the compound of the formula I wherein X is Cl toproduce a compound of the formula I wherein X is H, and

(d) substituting Br or I, respectively, for H at the 5 and 5′ positionsof the compound of the formula I wherein X is H.

In its second aspect, the present invention is a process for making acompound of the formula IV

wherein

R¹ is C₁ to C₁₀ primary or secondary alkyl or cycloalkyl,

R⁴ is C₁ to C₁₀ primary or secondary alkyl or cycloalkyl, and

X is H, Cl, Br, or I

comprising:

(1) when X is H

(a) alkylating a compound of the formula V

 at the 4-position thereof to produce a compound of the formula VI

 wherein R³ is C₄ to C₂₀ tertiary alkyl,

(b) oxidatively coupling the compound of the formula VI to produce acompound of the formula VII

(c) dealkylating a compound of the formula VII to produce a compound ofthe formula IV wherein X is H; or

(2) when X is Cl, Br, or I

(a) alkylating a compound of the formula V at the 4-position thereof toproduce a compound of the formula VI,

(b) oxidatively coupling the compound of the formula VI to produce acompound of the formula VII,

(c) dealkylating a compound of the formula VII to produce a compound ofthe formula IV wherein X is H, and

(d) substituting Cl, Br, or I, respectively, for H at the 5 and 5′positions of the compound of the formula IV wherein X is H.

In its third aspect, the present invention is a process for making acompound of the formula I

wherein

R¹ is C₁ to C₁₀ primary or secondary alkyl or cycloalkyl,

R² is C₁ to C₁₀ primary or secondary alkyl or cycloalkyl, and

X is H,

comprising:

(a) oxidatively coupling a compound of the formula III

 wherein X is Cl, to produce a compound of the formula I wherein X isCl, and

(b) dechlorinating the compound of the formula I wherein X is Cl toproduce a compound of the formula I wherein X is H.

In another aspect the present invention is a compound selected from thegroup consisting of 3,3′,6,6′-tetramethyl-2,2′-biphenol, and3,3′-di-isopropyl-6,6′-dimentyl-2,2′-biphenol.

DETAILED DESCRIPTION OF THE INVENTION

The first aspect of the present invention provides a process forpreparing 3,3′,6,6′-tetraalkyl-2,2′-biphenol, comprising (1)substituting chlorine for hydrogen at the 4-position of2,5-dialkylphenol, (2) oxidatively coupling the resulting2,5-dialkyl-4-chloro-phenol, and (3) removing chlorine from theresulting compound. The second step is carried out by analogy with themethods of Sartori, et al (Tetrahedron, 1992, 48, 9483), but using thefree phenol rather than its dichloroaluminate derivative. The threesteps of the process are shown below.

wherein R¹ is C₁ to C₁₀ primary or secondary alkyl or cycloalkyl; and R²is C₁ to C₁₀ primary or secondary alkyl or cycloalkyl.

Preferred R¹ are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,cyclohexyl, and cyclopentyl. Preferred R² are methyl and ethyl. Thealkyl groups at the 2- and 5-postions may be the same or different.

In the first step of the process, a 2,5-dialkylphenol can be reactedwith a chlorinating agent, such as chlorine or sulfuryl chloride,preferably in the presence of 1 to 10 mol % of a catalyst such asaluminum chloride or a diaryl sulfide such as diphenyl sulfide or amixture thereof. See Watson, J. Org. Chem., 1985, 50, 2145. The reactionmay be conducted neat (without a solvent) or in a medium such asdichloromethane, chlorobenzene, or other inert solvent at a temperaturebetween −30 and 60° C., preferably at about 25° C. The reaction istypically performed at or about atmospheric pressure for ease ofoperation.

In the second step of the process, the resulting2,5-dialkyl-4-chlorophenol can be oxidatively coupled to give thecorresponding dimeric chlorophenols(5,5′-dichloro-3,3′,6,6′-tetraalkyl-2,2′-biphenol). The preferred methodfor oxidative coupling of the chlorinated phenols is by the use of aniron(III) salt, preferably ferric chloride, in a suitable polar, aproticsolvent such as dichloromethane or nitromethane, preferably nitromethaneat temperature between 0° C. and 60° C., preferably about 35° C. Theproduct is isolated by dilution with water and filtration.

In the third step of the process, dechlorination of5,5′-dichloro-3,3′,6,6′-tetraalkyl-2,2′-biphenols can be accomplished byhydrogenolytic reduction to provide the required3,3′,6,6′-tetraalkyl-2,2′-biphenols. The reduction is carried out in thepresence of hydrogen gas, preferably at pressures between 1 and 50atmospheres and temperature between 5° and 80° C., and a formate salt,such as sodium formate, and Raney® nickel or palladium catalyst such aspalladium hydroxide on carbon. If a palladium catalyst is used, thereaction is generally carried out in a protic solvent such as methanol,containing 1.0 to 4.0 equivalents of an amine such as triethylamine toabsorb the hydrogen chloride produced in the reaction.

The second aspect of the present invention provides a process forpreparing a compound of the formula IV, comprising (1) substituting atertiary alkyl group for hydrogen at the 4-position of2,5-dialkylphenol, (2) oxidatively coupling the resulting2,5-dialkyl-4-tert-alkyl-phenol, and (3) removing the tertiary alkylgroup from the resulting compound. The three steps of the process areshown below.

wherein R¹ is C₁ to C₁₀ primary or secondary alkyl or cycloalkyl; R⁴ isC₁ to C₁₀ primary or secondary alkyl or cycloalkyl; and R³ is C₄ to C₂₀tertiaryl alkyl.

In the first step of the process, a 2,5-dialkylphenol can be reactedwith a tert-alkyl halide in the presence of a Lewis Acid catalyst, suchas zinc chloride or aluminum chloride, to give a2,5-dialkyl-4-tert-alkylphenol. Alternatively, the2,5-dialkyl-4-tert-alkylphenol can be prepared from contacting2,5-dialkylphenol with 2,2-dialkylethylene in the presence of an acidcatalyst. An example of the alternative method is the incorporation of atert-butyl group into the 4-position of 2,5-dialkylphenol by reacting2,5-dialkylphenol with isobutylene in the presence of sulfuric acid.

In the second step of the process, 2,5-dialkyl-4-tert-alkylphenol can beoxidatively coupled using a copper diamine catalyst and oxygen as theoxidizing agent.

The copper diamine catalyst can be prepared using the proceduredescribed in the Tetrahedron Letters, 1994, 35, 7983. A copper halide,such as CuCl, CuBr, CuI, or CuCl₂, is added to a mixture of alcohol,such as methanol, and water and the diamine is slowly added. After theaddition of the diamine, air is sparged through the mixture withvigorous stirring. The catalyst is filtered. Additional catalyst can beobtained by concentrating the filtrate and filtering the desiredcatalyst. The catalyst can also be prepared in situ by contacting thecopper halide and the diamine in the solvent for the coupling reaction.Suitable solvents for the oxidative coupling of tri and tetrasubstitutedphenols are methylene chloride and aromatic solvents such as xylene,benzene and toluene. Example of diamines include, but are not limitedto, the following: N,N,N′,N′-tetraethylethylene diamine,N,N,N′,N′-tetraethyl-1,3-propanediamine, N,N,N′,N′-tetraethylmethanediamine, N,N,N′,N′-tetramethyl-1,6-hexanediamine,N,N,N′,N′-tetramethyl-1,3-propanediamine, dipiperidinomethane,N,N,N′,N′-tetramethylethylene diamine and1,4-diazabicyclo-(2,2,2)-octane. Preferrably, the diamine isN,N,N′,N′-tetramethylethylene diamine.

In the third step of the process, the3,3′,6,6′-tetraalkyl-5,5′-di-tert-alkyl-2,2′-biphenol can be dealkylatedby contacting it with a strongly acidic catalyst, such as an alkyl- orarylsulfonic acid, sulfuric acid, phosphoric acid, aluminum chloride, orthe like, optionally in the presence of a solvent such as toluene,chlorobenzene, nitromethane, or xylene, typically at temperaturesbetween 10 and 150° C.

The oxidative coupling can be carried out neat (without a solvent) orusing one or more of a wide range of poorly oxidizable solventsincluding dichloromethane, chlorobenzene, toluene, xylenes,nitromethane, paraffins, etc. Static air, air-flow, or oxygen can beused as oxidants in the oxidative coupling.

The third aspect of the present invention provides a process for makinga compound of the formula I

wherein

R¹ is C₁ to C₁₀ primary or secondary alkyl or cycloalkyl,

R² is C₁ to C₁₀ primary or secondary alkyl or cycloalkyl, and

X is H,

comprising:

(a) oxidatively coupling a compound of the formula III

 wherein X is Cl, to produce a compound of the formula I wherein X isCl, and

(b) dechlorinating the compound of the formula I wherein X is C toproduce a compound of the formula I wherein X is H.

In the first step of the process, the resulting2,5-dialkyl-4-chlorophenol can be oxidatively coupled to give thecorresponding dimeric chlorophenols(5,5′-dichloro-3,3′,6,6′-tetraalkyl-2,2′-biphenol). The preferred methodfor oxidative coupling of the chlorinated phenols is by the use of aniron(III) salt, preferably ferric chloride, in a suitable polar, aproticsolvent such as dichloromethane or nitromethane, preferably nitromethaneat temperature between 0° C. and 60° C., preferably about 35° C. Theproduct is isolated by dilution with water and filtration.

In the second step of the process, dechlorination of5,5′-dichloro-3,3′,6,6′-tetraalkyl-2,2′-biphenols can be accomplished byhydrogenolytic reduction to provide the required3,3′,6,6′-tetraalkyl-2,2′-biphenols. The reduction is carried out in thepresence of hydrogen gas, preferably at pressures between 1 and 50atmospheres and temperature between 5° and 80° C., and a formate salt,such as sodium formate, and Raney® nickel or palladium catalyst such aspalladium hydroxide on carbon. If a palladium catalyst is used, thereaction is generally carried out in a protic solvent such as methanol,containing 1.0 to 4.0 equivalents of an amine such as triethylamine toabsorb the hydrogen chloride produced in the reaction.

In the first, second and third aspects of the present invention, a3,3′,6,6′-tetraalkyl-5,5′-dihalo-2,2′-biphenol may be halogenated at thepara positions of 3,3′,6,6′-tetraalkyl-2,2′-biphenol, as shown below,

wherein R¹ is C₁ to C₁₀ primary or secondary alkyl or cycloalkyl; R² isC₁ to C₁₀ primary or secondary alkyl or cycloalkyl; and X is Cl, Br orI.

Addition of Br to 3,3′,6,6′-tetraalkyl-2,2′-biphenols can beaccomplished by reaction of Br₂ in a suitable solvent. Typical solventsfor bromination are low polarity solvents such as chloroform,dichloromethane, carbon tetrachloride, and carbon disulfide. In somecases, aqueous bromine can be used. The preferred process is one carriedout in a low polarity solvent. This reaction can be accomplished at −10°C. to 50° C., preferably at room tempearature.

The compounds which are produced by the processes of the presentinvention can be used as reactants to make phosphorous-containingligands that are useful to make catalysts that, in turn, are useful inboth hydrocyanation and hydroformylation reactions. Bidentate phosphiteligands are particularly useful.

Bidentate phosphite ligands can be prepared as described in U.S. Pat.No. 5,235,113 by contacting phosphorochloridites with the biphenolcompounds made by the processes of the present invention. More recentU.S. Pat. Nos. 6,031,120 and 6,069,267, incorporated herein byreference, describe selective synthesis of bidentate phosphite ligandsin which a phosphorochloridite is prepared in-situ from phosphorustrichloride and a phenol such as o-cresol and then treated in the samereaction vessel with an aromatic diol to give the bidentate phosphiteligand. The biphenols of the present invention are substituted for thearomatic diol.

The compounds which are produced by the processes of the presentinvention can be polymerized and then used as reactants to makephosphorous-containing ligands that are useful to make catalysts that,in turn, are useful in both hydrocyanation and hydroformylationreactions.

The compounds made by the processes of the present invention, in which Xis H, can be used to make polymeric ligands by a process whichcomprises: (1) reacting the compounds made by the processes of thepresent invention, in which X is H, with a compound containing at leasttwo benzyl chloride groups, in the presence of a Lewis acid catalyst,and (2) reacting the product of step (1) with at least onephosphorochloridite compound in the presence of an organic base.Preferably the Lewis acid catalyst is zinc chloride or aluminumchloride, and the organic base is a trialkylamine.

The compounds made by the processes of the present invention, in which Xis Cl, Br, or I, can be used to make polymeric ligands by a processwhich comprises:

(1) protecting the OH groups by substituting a lower alkyl protectinggroup for H on the OH groups to make a protected compound,

(2) treating the protected compound with a compound containing at leasttwo boronic groups in the presence of a Group VIII transition metalcatalyst,

(3) replacing the protecting group of the product from step (2) withhydrogen, and

(4) reacting the product of step (3) with at least onephosphorochlorodite compound in the presence of an organic base.

Preferably, the Group VIII transition metal is palladium, nickel orcopper and the organic base is a trialkylamine compound in which thealkyl group is a C₁ to C₁₂ branched or straight chain alkyl group. Morepreferably the organic base is triethylamine.

Two particularly important industrial catalytic reactions usingphosphorus-containing ligands are olefin hydrocyanation andisomerization of branched nitrites to linear nitrites. See, for example,U.S. Pat. Nos. 5,512,695 and 5,512,696, and International PatentApplication WO9514659. Phosphite ligands are particularly useful forboth reactions. The hydrocyanation of unactivated and activatedethylenically unsaturated compounds (olefins) using transition metalcomplexes with monodentate and bidentate phosphite ligands is wellknown. Bidentate phosphinite and phosphonite ligands are useful as partof a catalyst system for the hydrocyanation of ethylenically unsaturatedcompounds. Bidentate phosphinite ligands are also useful as part of acatalyst system for the hydrocyanation of aromatic vinyl compounds.

Hydroformylation is another industrially useful process that utilizescatalysts made from phosphorus- containing ligands. The use of phosphineligands, including diphosphines, is known for this purpose. The use ofcatalysts made from phosphite ligands is also known. Such catalystsusually contain a Group VIII metal. See for example, U.S. Pat. No.5,235,113.

Two particularly useful compounds that can be made by the presentprocesses are 3,3′,6,6′-tetramethyl-2,2′-biphenol and3,3′-di-isopropyl-6,6′-dimentyl-2,2′-biphenol.

EXAMPLES

The following non-limiting examples illustrate the present invention.All parts, proportions, and percentages are by weight, unless otherwiseindicated.

Example 1 Process in Accordance With the First Aspect of the Inventionfor Preparing 3,3′,6,6′-Tetramethyl-2,2′-biphenol

First Step of the Process: Preparation of 4-Chloro-2,5-Xylenol:

To a solution of 100 g (0.82 mol) of 2,5-xylenol and 0.9 g of diphenylsulfide in 700 mL of dichloromethane was added a solution of 106 g (0.79mol) of sulfuryl chloride in 100 mL of dichloromethane, maintaining thetemperature at 5-15° C. The mixture was stirred for an additional hourand then poured onto 400 g of ice-water containing 5 g of sodiumbisulfite. The layers were separated, and the organic phase was washedwith water, dried (MgSO₄), and concentrated to dryness. The crude solidswere slurried with a minimum amount of hexanes, filtered, andsuction-dried to give 121 g (94%) of product, homogeneous by Thin LayerChromatography (TLC), GC, and ¹H-NMR analysis. ¹H-NMR (CDCl₃) δ 2.18 (s,3H), 2.27 (s, 3H), 4.61 (s, 1H), 6.63 (s, 1H), 7.07 (s, 1H). Lit(Blackstock, Aust. J. Chem. 1973, 26, 775): mp 74-75° C.

Second Step of the Process: Preparation of 5,5′-Dichloro-3,3′,6,6′-Tetramethyl-2,2′-Biphenol

To a mechanically-stirred mixture of 71.4 g (0.458 mol) of4-chloro-2,5-xylenol and 120 mL of nitromethane was added 94 g (0.59mol) of anhydrous ferric chloride in portions over about 20 minutes withcooling to maintain the temperature below 35° C. The mixture was stirredfor an additional 3 hours and then 300 mL of ice water containing 50 mLof concentrated HCl was added, followed by 300 mL of hexanes. Themixture was filtered, and the solids were washed with water and hexanesand dried in vacuo to give 51.0 g of product. The organic phase wasseparated from the filtrate, washed with water, and concentrated; theresidue was then slurried in hexanes and filtered to give another 11 gof product. The total yield was thus 62 g (87%) of a tan solid (mp148-155° C.). Additional purification to remove traces of iron helpsfacilitate the subsequent reductive dechlorination. Purification couldbe accomplished by dissolving in ethyl acetate, washing this solutionwith aqueous ethylenediamine-tetraacetic acid disodium salt (EDTA-2Na,EDTA=ethylenediaminetetraacetic acid), drying (MgSO₄), concentration andwashing with hexanes to afford off-white material with mp 164° C. ¹H-NMR(CDCl₃) δ 1.98 (s, 3H), 2.25 (s, 3H), 4.60 (s, 1H), 7.25 (s, 1H).

Third Step of the Process: Preparation of3,3′,6,6′-Tetramethyl-2,2′-Biphenol:

A sample of purified 5,5′-dichloro-3,3′,6,6′-tetramethyl-2,2′-biphenol(15.0 g, 48.4 mmol) was dissolved in 100 mL of ethanol containing 10 mLof water and 20 mL of triethylamine. This solution was added to 1.0 g(dry weight basis) of moist 20% Pd(OH)₂/C (Pearlman's catalyst) andhydrogenated at 50 psig for 2 hours at ambient temperature. The productwas isolated by filtration of catalyst, concentration, dissolution ofthe residue in EtOAc, washing with water, and concentration to drynessto give 11.0 g (94%) of product, mp 110-113° C. ¹H-NMR (CDCl₃) δ 1.95(s, 3H), 2.25 (s, 3H), 4.71 (s, 1H), 6.81 (d, 1H, J=7.5 Hz), 7.10 (d,1H, J=7.5 Hz).

The second and third steps of the foregoing example also illustrate thethird aspect of the invention.

Example 2 Process in Accordance With the Third Aspect of the Inventionfor Preparing 3,3′-di-Isopropyl-6,6′-dimethyl-2,2′-biphenol

First Step of the Process: Preparation of5,5′-Dichloro-3,3′-diisopropyl-6,6′-dimethyl-2,2′-biphenol:

A well-stirred mixture of 36.0 g (0.195 mol) of chlorothymol and 50 mLof nitromethane was cooled to 5° C. and 40 g (0.25 mol) of anhydrousferric chloride was added over 20 minutes. The mixture was allowed towarm to ambient temperature and held an additional hour. Ice-water (300mL) was added all at once, and the mixture was concentrated at reducedpressure to remove about 100 mL of the nitromethane-water azeotrope. Thesolids were filtered and recrystallized from aqueous isopropanol to give23.3 g of a first crop and 3.9 g of a second crop of solids, mp 98° C.¹H-NMR (CDCl₃) δ 1.24 (two d, 6H, J=7 Hz), 1.98 (s, 3H), 3.26 (septet,1H, J=7 Hz), 4.63 (s, 1H), 7.30 (s, 1H).

Second Step of the Process:3,3′-di-Isopropyl,6,6′-dimethyl-2,2′-biphenol:

This substituted biphenol was prepared similarly to the third step ofExample 1 except5,5′-dichloro-3,3′-diisopropyl-6,6′-dimethyl-2,2′-biphenol was usedinstead of 5,5′-dichloro-3,3′,6, 6′-tetramethyl-2,2′-biphenol, mp 89-92°C. ¹H-NMR (CDCl₃) δ 1.25 (d, 6H), 1.95 (s, 3H), 3.28 (septet, 1H), 4.76(s, 1H), 6.88 (d, 1H, J=7.5 Hz), 7.18 (d, 1H, J=7.5 Hz).

Example 3 Process in Accordance With the Second Aspect of the Inventionfor Preparing 3,3′,6,6′-Tetramethyl-2,2′-biphenol

First Step of the Process: Preparation of 4-t-Butyl-2,5-xylenol

Preparation of 4-t-Butyl-2,5-xylenol: 2,5-Xylenol (90 g, 0.73 mol) wasmelted at 80° C., 1 mL of concentrated sulfuric acid was added, and themixture was heated at 90° C. while isobutylene gas was introducedsubsurface over 4 hours. The reaction appeared to stall at about 80%conversion. The reaction mass was diluted with water and neutralizedwith NaHCO₃, and some starting xylenol was removed bysteam-distillation. Since the steam-distillation did not completelyremove the starting material, the residue was dissolved in hot hexanes,separated from the aqueous phase, and cooled in an ice-bath. Theprecipitated product was filtered and washed with cold hexanes to give64 g (49%) of 4-t-Butyl-2,5-xylenol; lit. (Stevens, Ind. Eng. Chem.1943, 655; Parc, Rev. Inst. Fr. Pet. 1960, 680) mp 70-72° C. ¹H-NMR(CDCl₃) δ 1.37, (s, 9H), 2.20 (s, 3H), 2.43 (s, 3H), 4.85 (s, 1H), 6.53(s, 1H), 7.08 (s, 1H).

Second Step of the Process: Preparation of5,5′-Bis(t-butyl)-3,3′,6,6′-tetramethyl-2,2′-biphenol:

To a solution of 18.6 g (0.104 mol) of 4-t-butyl-2,5-xylenol in 20 mL ofdichloromethane was added 0.6 g (3 mmol) of copper chlorohydroxide-TMEDAcomplex (TMEDA=tetramethylethylenediamine). The dark purple mixture wasstirred under ambient air overnight. Gas chromatography (GC) analysisshowed only 25% conversion, so the mixture was diluted withdichloromethane, dried (MgSO₄) and concentrated to dryness. To the cruderesidue was added 20 mL of cyclohexane and 1.2 g (6 mmol) of the abovecopper chlorohydroxide-TMEDA catalyst, and the mixture was stirred underair at ambient temperature for three days (85% conversion). The purplesolution was concentrated to dryness, and the residue waschromatographed on silica gel to give 10.2 g (55%) of pure5,5′-Bis(t-butyl)-3,3′,6,6′-tetramethyl-2,2′-biphenol, mp 103-105° C.¹H-NMR (CDCl₃) δ 1.42, (s, 9H), 2.06 (s, 3H), 2.25 (s, 3H), 4.54 (s,1H), 6.51 (s, 1H), 7.24 (s, 1H).

Third Step of the Process: Preparation of3,3′,6,6′-Tetramethyl-2,2′-biphenol:

To a 50 mL flask were added 0.5 g of5,5′-Bis(t-butyl)-3,3′,6,6′-tetramethyl-2,2′-biphenol, 5 mL of xylenesand 0.05 g of p-toluenesulfonic acid. The mixture was refluxed for about2 hours. The mixture was cooled and water added. The mixture wasextracted with hexanes; the organic layer was washed with water anddried over MgSO₄. After removing the solvent, the residue wasrecrystallized from petroleum ether.

Example 4 Process in Accordance With the Second Aspect of the Inventionfor Preparing5,5′-Di-t-butyl-3,3′-di-isoprbpyl,6,6′-dimethyl-2,2′-biphenol

First Step of the Process: Preparation of 4-t-Butylthymol:

To 30 g (0.20 mol) of thymol, heated at 60° C. under nitrogen, was added1 g of concentrated sulfuric acid. After heating to 90° C., a slowstream of isobutylene was introduced over about 2 hours. The reactionstalled at about 50% conversion, so an additional charge of sulfuricacid was added and the reaction was monitored by GC-analysis untilapproximately 70-80% conversion was achieved. The reaction was worked upas in Example 1 and the crude residue was recrystallized from hexanes togive 20 g of 4-t-butylthymol, mp 68-69° C., lit (U.S. Pat. No.4,880,775): mp 76-77° C. ¹H-NMR (CDCl₃) δ 1.25 (d, 6H, J=7 Hz), 1.38,(s, 9H), 2.44 (s, 3H), 3.15 (septet, 1H), 4.49 (s, 1H), 6.51 (s, 1H),7.18 (s, 1H).

Second Step of the Process: Preparation of5,5′-Di-t-butyl-3,3′-di-isopropyl,6,6′-dimethyl-2,2′-biphenol:

To a solution of 20 g (0.104 mol) of 4-t-butylthymol in 50 mL ofdichloromethane was added 1.0 g (5 mmol) of copper chlorohydroxide-TMEDAcomplex and the dark purple mixture was allowed to stir under ambientair for three days (50% conversion). The mixture was diluted withhexanes, washed with aqueous EDTA solution, dried (MgSO₄) andconcentrated to dryness. The residue was chromatographed on silica gelto give 3.6 g (34% based on conversion) of pure dimer5,5′-Di-t-butyl-3,3′-di-isopropyl,6,6′-dimethyl-2,2′-biphenol, mp105-108° C. ¹H-NMR (CDCl₃) δ 1.26 (d, 6H) 1.43, (s, 9H), 3.25 (septet,1H), 4.58 (s, 1H), 7.30 (s, 1H).

Debutylating5,5′-di-t-Butyl-3,3′-diisopropyl-6,6′-dimethyl-2,2′-biphenol

A 500-mL resin kettle equipped with mechanical stirrer and condenser wasplaced in an oil bath and charged with 153 g of a mixture of5,5′-di-t-butyl-3,3′-diisopropyl-6,6′-dimethyl-2,2′-biphenol in ahydrocarbon solvent. By gas chromatography analysis, the mixture was15.0% 5,5′-di-t-butyl-3,3′-di-isopropyl,6,6′-dimethyl-2,2′-biphenol. 1.5g p-toluenesulfonic acid was charged, and the mixture was heated to 130°C. After 7.5 hours, gas chromatography analysis showed the mixturecontained 11.6% fully debutylated product,3,3′-diisopropyl-6,6′-dimethyl-2,2′-biphenol; 2.7% mono-debutylatedproduct, 5-t-butyl-3,3′-diisopropyl-6,6′-dimethyl-2,2′-biphenol; and0.3% unreacted starting material.

Example 5 Bromination of2,2′-Dihydroxy-3,3′-diisopropyl-5,5′-dimethylbiphenyl

Under an atmosphere of nitrogen, Br₂ (3.36 mL, 0.0652 mol) in CH₂Cl₂ (5mL) was added dropwise to a CH₂Cl₂ (200 mL) solution of2,2′-dihydroxy-3,3′-diisopropyl-5,5′-dimethylbiphenyl (6.488 g, 0.0217mol). The resulting mixture was stirred at room temperature overnight.After the reaction was complete, the mixture was washed with 10% NaHSO₃(3×50mL) followed by brine (2×50 mL) and dried over MgSO₄. The solventwas removed under vacuum to afford an orange oil, which was purified bycolumn chromatography.(silica gel, 10% EtOAc/hexane). Yield oflight-brown solid was 3.95 g (40%). ¹H NMR (C₆D₆): 1.07 (d, 6H), 1.89(s, 3H), 3.17 (m, 1H) 4.30 (br s, 1H), 7.52 (s, 1H).

What is claimed is:
 1. A process for making a compound of the formula IV

wherein R¹ is C₁ to C₁₀ primary or secondary alkyl or cycloalkyl, R⁴ isC₁ to C₁₀ primary or secondary alkyl or cycloalkyl, and X is H, Cl, Br,or I comprising: (1) when X is H (a) alkylating a compound of theformula V

 at the 4-position thereof to produce a compound of the formula VI

 wherein R³ is C₄ to C₂₀ tertiary alkyl, (b) oxidatively coupling thecompound of the formula VI to produce a compound of the formula VII

(c) dealkylating a compound of the formula VII to produce a compound ofthe formula IV wherein X is H; and (2) when X is Cl, Br, or I (a)alkylating a compound of the formula V at the 4-position thereof toproduce a compound of the formula VI, (b) oxidatively coupling thecompound of the formula VI to produce a compound of the formula VII, (c)dealkylating a compound of the formula VII to produce a compound of theformula IV wherein X is H, and (d) substituting Cl, Br, or I,respectively, for H at the 5 and 5′ positions of the compound of theformula IV wherein X is H.
 2. The process of claim 1 wherein thealkylating step is carried out by reacting the compound of the formula Vwith a tert-alkyl halide in the presence of a Lewis Acid catalyst. 3.The process of claim 2 wherein the Lewis Acid catalyst is zinc chlorideor aluminum chloride.
 4. The process of claim 1 wherein the alkyatingstep is carried out by reacting the compound of the formula V with a2,2-dialkylethylene in the presence of an acid catalyst.
 5. The processof claim 1 wherein the oxidative coupling step is carried out byexposing the compound of the formula VI to oxygen and a copper diaminecatalyst.
 6. The process of claim 1 wherein the dealkylating step iscarried out by contacting the compound of the formula VII with a strongacid selected from the group consisting of alkylsulforic acid,arylsulforic acid, sulfuric acid, phosphoric acid, and aluminumchloride.
 7. The process of claim 6 wherein the strong acid is selectedfrom the group consisting of alkylsulfonic acid, arylsulfonic acid,sulfuric acid, phosphoric acid, and aluminum chloride.